Inflammation is the reaction of living tissue to infection or injury, normally resulting in healing and the restoration of tissue structure and function. Inflammation also involves a complex set of responses which neutralize and remove pathogens and lead to the repair of the affected area. Symptoms of inflammation include pain, heat, redness, swelling, and dysfunction. Vascular dilation occurs, together with exudation of fluid and certain cellular components of blood into the surrounding tissue.
Most inflammatory states are characterized by the presence of neutrophils, or polymorphonuclear leukocytes (PMN).
Inflammation occurs in the initial stages of wound healing and is an integral part of the wound-healing process. Inflammation promotes the formation of granulation tissue. The earliest steps in this inflammatory response involve the influx of neutrophils into the wound space. Although PMN are important in phagocytizing wound debris and bacterial contaminants, their exact role in wound healing is unclear.
Inflammation is also associated with a number of disease states. In some diseases, such as pneumonia, inflammation is important to eradication of infection and ultimate survival of the patient. In other diseases, unchecked inflammation may be detrimental, probably due to tissue injury caused by the oxidants and proteolytic enzymes released by PMN. In these latter conditions, a reduction in inflammation is beneficial to the patient. Examples of such disease states include arthritis and other inflammatory joint diseases, adult respiratory distress syndrome and idiopathic pulmonary fibrosis.
Lung inflammation is characterized by the presence of PMN in the pulmonary interstitium and airspaces. For example, interstitial and airspace neutrophils are a hallmark of adult respiratory distress syndrome (ARDS) (Pistorese et al., Chest 88: A86, 1985; Maunder et al., Am. Rev. Resoir. Dis. 135: A260, 1987). Severity of ARDS is proportional to the number of neutrophils in the lungs, and patients who have fewer airspace neutrophils relative to airspace macrophages have a better rate of survival (Maunder et al., Am. Rev. Respir. Dis. 139: A221, 1989). Neutrophil influx also appears to be involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF) (Bitterman et al., J. Clin. Invest. 72: 1801-1813, 1983; Hunninghake et al., J. Clin. Invest. 68: 259-269, 1981).
A major role for neutrophils in the symptoms of inflammation is suggested by studies of Job's syndrome, a congenital defect in PMN chemotaxis (Hill et al., Lancet 2: 617-619, 1974). Patients with this condition experience recurrent "cold abscesses" without the usual associated symptoms of inflammation. In addition, patients with diabetes mellitus and patients receiving corticosteroid therapy have impaired response to infection, which may be related to impaired PMN chemotaxis.
Two classes of chemotactically active molecules that can recruit PMN from the bloodstream into the lungs have been identified. A low molecular weight human lipid was identified by Hunninghake et al. (J. Clin. Invest. 66: 473-483, 1980), and has subsequently been identified as leukotriene B.sub.4 (LTB.sub.4) (Martin et al., Am. Rev. Respir. Dis. 129: 106-111, 1984; Martin et al., J. Clin. Invest. 80: 1114-1124, 1987). A protein with a molecular weight of approximately 10,000 Daltons produced by human alveolar macrophages has been described (Merrill, et al., J. Clin. Invest. 65: 268-276, 1980) but has not been precisely identified or characterized.
Recently, four different groups have isolated homologous low molecular weight (6-10 kDa) peptide chemoattractants from LPS-stimulated human peripheral blood monocytes (Yoshimura et al., J. Immunol. 139: 788-793, 1987; Schroder et al., J. Immunol. 139: 3474-3483, 1987; Yoshimura et al., Proc. Natl. Acad. Sci. USA 84: 9233-9237, 1987; Matsushima et al., J. Exp. Med. 167: 1883-1893, 1988; Walz et al., Biochem. Biophys. Res. Comm. 149: 755-761, 1987; Thelen et al., FASEB J. 2: 2702-2706, 1988; Peveri et al., J. Exp. Med. 167: 1547-1549, 1988; Lindley et al., Proc. Natl. Acad. Sci. USA 85: 9199-9203, 1988; Van Damme et al., J. Exp. Med. 167: 1364-1376, 1988; Schroder et al., Biochem. Biophys. Res. Comm. 152: 277-284, 1988) that are identical to the amino acid sequence inferred from the 3-10C cDNA sequence reported by Schmid et al., (J. Immunol. 139: 250-256, 1987). The protein has now been called NAP-1.
Experimental evidence suggests that the production of particular chemoattractants is determined by the nature and duration of the inflammatory stimulus. Thus, efforts to control the production or activity of only one of these chemoattractants (e.g. LTB.sub.4) may be ineffective in regulating an inflammatory response.
There remains a need in the art for substances that can either promote or reduce inflammation. Those that promote inflammation may find utility in speeding the healing of wounds or aiding recovery from pneumonia. Promotion of inflammation may be particularly desirable in patients with defects in PMN chemotaxis, including diabetics, patients receiving steroid therapy, and patients with congenital chemotaxis defects (e.g. Job's syndrome). Anti-inflammatory agents would find utility in the treatment of certain inflammatory lung diseases. Because alveolar macrophage-derived chemoattractants are likely to be important in mediating neutrophil migration and the resultant lung injury, efforts to interrupt this inflammatory process would require an understanding of all mechanisms of neutrophil chemotaxis.